DE2845770A1 - NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein R1 is (a) hydrogen, (b) C1-10 alkyl, (c) C1-10 alkyl substituted by halogen; C1-4 alkoxy; C6-10 aryl; C6-10 aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C1-4 alkoxy group; di-C1-4-alkylamino; or tri-C1-4-alkylammonium, (d) C4-10 cycloalkyl, (e) C4-10 cycloalkyl substituted by C1-4 alkyl, (f) C6-10 aryl, (g) C6-10 aryl substituted by 1-3 halogen atoms, a phenyl group 1-3 C1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C1-4 alkoxy group, or (h) an aromatic heterocycle of 5 or 6 ring atoms one of which is O, N or S; A is -CH2-CH2-, trans-CH=CH- or -C 3BOND C-; W is hydroxymethylene, RO-methylene, CH3 or CH3, <IMAGE> wherein OH or OR is in the alpha - or beta -position and R is an in vivo hydrolyzable and physiologically acceptable ether or acyl group which is conventional for modifying OH groups in prostaglandins; D and E together are a direct bond, or D is C1-10 alkylene, C1-10 alkenylene or C1-10 alkynylene or one of these groups substituted by fluorine, and E is oxygen, -C 3BOND C- or a direct bond; R2 is (a) a C1-10 hydrocarbon aliphatic radical, (b) a C6-10 hydrocarbon aliphatic radical substituted by C6-10 aryl or by C6-10 aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C1-4 alkoxy group; (c) C4-10 cycloalkyl, (d) C4-10 cycloalkyl substituted by C1-4 alkyl, (e) C6-10 aryl, (f) C6-10 aryl substituted by 1-3 halogen atoms, a phenyl group, 1-3 C1-4 alkyl groups or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C1-4 alkoxy group; or (h) an aromatic heterocycle of 5 or 6 ring atoms one of which is O, N or S; and R3 is OH or OR; and, when R1 is hydrogen, the salts thereof with physiologically compatible bases, are effective as antihypertensive, bronchiodilators, thrombocyte aggregation inhibitors, inter alia.

Description

-H-

The invention relates to new prostacyclin derivatives and processes for their Manufacture and their use as pharmaceuticals.

Prostacyclin (PGIp), a major factor in platelet aggregation has a dilating effect on various blood vessels (Science 196., IO72) and is therefore to be regarded as a means of lowering blood pressure. PGI besH but not the stability necessary for a drug. The half-life of PGI is “at physiological pH values and at barely any temperature just a few minutes.

It has been found that the replacement of the 9-ether oxygen atom in prostacyclin stabilizes the prostacyclin through a methylene group, whereby the pharmacological spectrum of action is retained and the duration of action is significantly extended.

The compounds according to the invention have an antihypertensive and bronchodilator effect. They are also suitable for inhibiting platelet aggregation.

The invention relates to prostane derivatives of the general formula I

COOH ₁

CH

AWDEH.
d.

where 5

E _{1 is} hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical

can mean
A is a -CH ₂ -CH ₂ -, trans-CH = CH or -CSC group, W is a free or functionally modified hydroxymethylene group or

C ¹ TT a free or functionally modified \ J

-C- group, the OH group being OH

030018/0323

is α-constant,

D and E together are a direct bond or D is a straight-chain or branched, saturated or unsaturated one Alkylene group with 1-10 carbon atoms, which is optionally substituted by fluorine atoms,

E is an oxygen atom or a -CSG bond or a direct bond,

Ep is an alkyl, cycloalkyl or an optionally substituted one Aryl or a heterocyclic group,

B-, a free or functionally modified hydroxyl group, and if B ^ has the meaning of a hydrogen atom, its salts with physiological compatible bases mean.

As alkyl group B ^ are straight or branched alkyl groups with 1-10 Consider carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, heptyl, hexyl, decyl. The alkyl groups B ^ can optionally be substituted one to more than once by Halogen atoms, alkoxy groups, optionally substituted aryl groups, Dialkylamines and trialkylammonium. Preferred are those alkyl groups which are simply substituted.

Examples of substituents which may be mentioned are fluorine, chlorine or bromine atoms, phenyl, dimethylamine, diethylamine, methoxy, ethoxy. Preferred alkyl groups E ₁ are those with 1- * f carbon atoms, such as methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.

As aryl groups E, both substituted and unsubstituted aryl groups come into consideration, such as phenyl, 1-naphthyl and 2-naphthyl, each of which can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups, each with 1-k C- Atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with ± k carbon atoms. The substituents in the 3- and ^ -position on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the ^ -position by hydroxy, are preferred.

030018/0323 ,,

The cycloalkyl group R ₁ can contain 4-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups having 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl. Suitable heterocyclic groups R ₁ are 5- and 6-membered heterocycles which contain at least 1-heteroatora, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and others

The hydroxyl groups R-, and in W can be functionally modified, for example by etherification or esterification, the free or modified hydroxyl groups in W are in the α position, free hydroxyl groups being preferred. As ether and acyl residues the radicals known to the person skilled in the art come into consideration. Easily split off ether residues such as tetrahydropyranyl, Tetrahydrofuranyl-, α-ethoxyethyl-, trimethylsilyl-, dimethyl-tert, -butylsilyl- and tribenzyl-silyl radical. Examples of possible acyl radicals are: acetyl, propionyl, butyryl, benzoyl.

As the alkyl group R_ there are straight and branched chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1-7, carbon atoms, which are optionally substituted by optionally substituted Aryl can be substituted. Examples include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, Heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl, Benzyl and p-chlorobenzyl.

The cycloalkyl group R _? can contain 4-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups having 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methyl-cyclohexyl and adamantyl.

030018/0323

As substituted or unsubstituted aryl groups R _? for example: phenyl, 1-naphthyl and 2-naphthyl, each of which can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1 * 1 carbon atoms, a chloromethyl, fluoromethyl , Trifluoromethyl, carboxyl, alkoxy or hydroxyl group. Substitution in the 3- and * t-positions on the phenyl ring is preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the ^ -position by hydroxy. Suitable heterocyclic groups R_ are 5- and 6-membered heterocycles which contain at least one heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl-, ^ -pyridyl, among others

As the alkylene group D, there are straight-chain or branched-chain, saturated ones and unsaturated alkylene radicals, preferably saturated with 1-10, in particular 1-5 C atoms, which may optionally be substituted by fluorine atoms. Examples include: methylene, fluoromethylene, ethylene, 1.2-propylene, ethylethylene, trimethylene, tetramethylene, pentamenthylene, 1-methyl-tetramethylene, 1-methyl-trimethylene.

For salt formation with the free acids (R ₁ = H), inorganic and organic bases are suitable, as are known to the person skilled in the art for the formation of physiologically compatible salts. Examples include: alkali hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethynolamine, N-methylglücamin, morpholine, tris (hydroxymethyl) methylamine, etc.

The invention also relates to a method for producing the invention Prostane derivatives of the general formula I, characterized in that a compound of the general formula II,

r II

-A-W-D-E-R,

1> / Ü323

wherein R ", R- ,, A, V /, D and E have the meanings given above, optionally after protecting any free hydroxyl groups present with a Wittig reagent of the general formula III

Ph ₃ P = CH- (CH ₂ ) ₃ -c (qe in,

where Ph denotes a phenyl group, reacts and optionally then separates and / or protected isomers in any order Releases hydroxyl groups and / or esterifies free hydroxyl groups, etherifies and / or esterifies a free carboxyl group and / or an esterified Carboxyl group saponified or a carboxyl group converted into a salt with a physiologically compatible base.

The reaction of the compound of general formula II with the Wittig reagent of the general formula III, which is obtained from the corresponding phosphoniura salt with methanesulfinylmethyl sodium or methanesulfinylmethyl potassium or potassium tert-butoxide in dimethyl sulfoxide is produced at temperatures from O C to 100 C, preferably at 20 C to 80 C, in an aprotic Solvent, preferably dimethyl sulfoxide or dimethylformamide, made. The Z- and E-configured olefins obtained are separated in the usual way, for example by column or layer chromatography.

The saponification of the prostaglandin esters is carried out by the methods known to the person skilled in the art, for example using basic catalysts. The ester group, in which R _{1 represents} an alkyl group with 1-10 carbon atoms, is introduced according to the methods known to the person skilled in the art. The carboxy compounds are reacted, for example, with diazo hydrocarbons in a manner known per se. The esterification with diazo hydrocarbons is carried out, for example, by mixing a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound in the same or in a different inert solvent, such as methylene chloride. After the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester is purified in the usual way. Diazoalkanes are either known or can be prepared by known methods / Örg.Reactions Bd. J5, pages 389-39Λ (195 * 0 /.

030018/0323,

s-

The introduction of the ester group R 1, in which R 1 represents a substituted or unsubstituted aryl group, takes place according to the methods known to the person skilled in the art. For example, the carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiiinide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform . The reaction is carried out at temperatures between -30.degree. C. and +50.degree. C., preferably at +10.degree.

The prostaglandin derivatives of the general formula I rait R .. in the meaning of a hydrogen atom can with appropriate amounts of the corresponding inorganic bases are converted into salts with neutralization. For example when dissolving the corresponding PG acids in water, one obtains which contains the stoichiometric amount of the base, after evaporating the water or after adding a water-miscible solvent, for example Alcohol or acetone, the solid inorganic salt.

For the preparation of an amine salt, which takes place in the usual way, is the PG acid, for example, dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine was added to this solution. The salt usually falls in solid form or becomes after evaporation of the Solvent isolated in the usual way.

The functional modification of the free OH groups takes place according to the Methods known to those skilled in the art. To introduce the ether protecting groups, for example, dihydropyran in methylene chloride or chloroform is used Use of an acidic condensing agent, such as p-toluenesulfonic acid, implemented. The dihydropyran is used in excess, preferably in an amount from 2 to 10 times the theoretical requirement. The reaction is usually complete after 15-30 minutes at 0 ° C.-30 ° C.

030018/0323 _{/ l0}

284577Q

The acyl protective groups are introduced by adding a compound of the general formula I in a manner known per se with a carboxylic acid derivative, such as acid chloride, acid anhydride and others.

The release of a functionally modified OH group to the compounds of the general formula I is carried out by known methods. For example, the elimination of ether protection groups in an aqueous solution is a organic acid, such as acetic acid, propionic acid, etc. or in an aqueous solution of an inorganic acid such as hydrochloric acid. To improve the solubility, it is expedient a water-miscible inert organic solvent was added. Suitable organic solvents are, for example, alcohols, such as Methanol and ethanol, and ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The cleavage is preferably carried out at temperatures between 20.degree. C. and 80.degree.

The cleavage of the silyl ether protective groups takes place, for example with tetrabutylammoniurafluorxd. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc. The cleavage is preferably carried out at temperatures between 0.degree. C. and 80.degree.

The saponification of the acyl groups is carried out, for example, with alkali or Alkaline earth carbonates or hydroxides in an alcohol or the aqueous Solution of an alcohol. Aliphatic alcohols such as, for example, methanol, ethanol, butanol, etc., preferably methanol, are suitable as alcohols. Potassium and sodium salts may be mentioned as alkali metal carbonates and hydroxides, but the potassium salts are preferred. As alkaline earth carbonates and Hydroxides are, for example, suitable calcium carbonate and calcium hydroxide and barium carbonate. The reaction takes place at -10 ° C to 70 ° C, preferably at 25 ° C.

030018/0 ^ 33

-41-

As a starting material for the process described above The ketone of the general formula II used can be prepared by adding an alcohol of the formula IV

It

IV

Ph

OH

(E.J.Corey et al., J.Amer.Chem.Soc. 93., 1 ^ 90 (I97l)) with dihydropyran in Presence of catalytic amounts of p-toluenesulfonic acid in the tetrahydropyranyl ether V convicted.

OTHP

OTo s

OTHP

OH

VI

HO

Ph

ÖTHP

VIII

VII

133018/3323

The lactone V is converted into lactol VI with diisobutylaluminum hydride at -7O ° C reduced by Wittig reaction with trxphenylphosphonium methylene is converted into the olefin VII. After conversion into the tosylate with p-toluenesulfonyl chloride in the presence of pyridine, one obtains through Reaction with potassium nitrite in dimethyl sulfoxide the 9ß-configured Alcohol IX made with p-toluenesulfonyl chloride in the presence of pyridine in the tosylate X is transferred. Implementation with diethyl malonate in The presence of potassium tert-butoxide provides the diester XI, which by Decarbalkoxylation with sodium cyanide in dimethyl sulfoxide in the ester XII is converted.

OH

CC

OTo s

OTHP

COOC ₂ H

OTHP

GTHP

XII

COOC ₂ H _n

COOC ₂ H

XI

COOC,

OTHP

OTHP

XIII

XIV

OTHP
XV

030018/0323

- ./15

Oxidative cleavage of the double bond in compound XII with sodium periodate in the presence of catalytic amounts of osmium tetroxide leads to aldehyde XIII, which is oxidized with Jones reagent to acid XIV, which is then esterified with diazomethane to give compound XV. By Dieckmann condensation of XV with potassium tert-butoxide in tetrahydrofuran an isomer mixture of the ketocarboxylic acid esters XVI and XVII is obtained, which is obtained by means of a decarbalkoxylation with lj ^ f-diazabicyclo / 2.2.2 / octane is converted in xylene into ketone XVIII as the only reaction product.

OTHP
XVI

OTHP XVII

Ph

OTHP XVIII

The elimination of the tetrahydropyranyl ether protective group yields the alcohol XIX, which is esterified with benzoyl chloride in the presence of pyridine to give the ester XX.

0
U

OH

O. / Ph

XIX

XXII

OH

OCOPh

XXI

- ^CH0 030018/0323

^ru XXIII

- Ik -

Hydrogenolytic cleavage of the benzyl ether in the presence of catalytic Amounts of acid gives the alcohol XXI, which after ketalization to compound XXII with Collins reagent is oxidized to aldehyde XXIII.

This aldehyde is with a phosphonate of the general formula XXIV

O O

ⁿ 3 ^ P-CH -CDER XXIV

CH O ^ ^dd

wherein D, E and R_ have the meaning given above, in one Olefinierungsreaktxon converted to a ketone of the general formula XXV.

XXV ÖCOPh

After reduction of the 15-keto group with zinc borohydride or sodium borohydride or reaction with alkyl magnesium bromide or alkyl lithium and epimer separation gives the 15a-alcohols XXVI (PG numbering).

XXVI

"ÖCOPh

After saponification of the ester group, for example with potassium carbonate in Methanol and ketal cleavage with aqueous acetic acid gives the ketone of the general formula XXVII,

XXVII

OH

030018/0323 ../15

\ irelches optionally after functional modification of the free hydroxyl groups, for example by etherification with dihydropyran or optionally hydrogenation of the double bond, into the compound of the general Formula II is converted.

The new prostacyclin derivatives of the general formula I are valuable Pharmaceuticals, since they have a better specificity compared to the corresponding prostaglandins with a similar spectrum of activity, and above all a significant one have longer effectiveness. Compared to PGI, they stand out characterized by greater stability. The good tissue specificity of the new prostaglandins is evident when examining smooth muscle organs, e.g. on the guinea pig ileum or on the isolated rabbit trachea, where significantly less stimulation can be observed than with the Application of natural prostaglandins of the E, A or F type. The new prostaglandin analogs have the properties typical of prostacyclins, such as lowering the peripheral arterial and coronary vascular resistance and thus lowering of systemic blood pressure without lowering stroke volume and coronary blood flow at the same time, inhibition

-the of platelet aggregation and inhibitionYBronchoconstriction, inhibition gastric acid secretion, antiallergic properties, lowering of the pulmonary vascular resistance and pulmonary blood pressure, promotion of kidney blood flow, increase of cerebral blood flow. aside from that The new prostaglandic analogs have antiproliferative properties.

In the case of intravenous injection into vigorous, hypoxic rats in doses of 5, The compounds according to the invention show 20 and 100 μg / kg body weight a stronger antihypertensive and longer lasting effect than PGE and PGA_, without causing cardiac arrhythmias like PGE diarrhea or PGAp.

In the case of intravenous injection into anesthetized rabbits, those according to the invention show Connections in comparison to PGE and PGA a stronger and considerable long-lasting lowering of blood pressure without affecting other smooth muscle Organs or organ functions are affected.

For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For example, tablets, coated tablets or capsules are suitable for oral administration.

The invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and carriers.

The active ingredients according to the invention should be used in conjunction with the Galenics known and common auxiliaries e.g. for the production of Serve blood pressure lowering.

030018/0323 ../17

Reference example 1

la) (IS, 5R, 6S, 7R) -6-Benzyloxymethyl-7- (tetrahydropyran-2-yl-oxy) -2-oxabicyclo / 3-3-Q7 octan-3-one

A solution of I ¹ I-, 5g (lS, 5R, 6S, 7R) -6-benzyloxymethyl-7-hydroxy-2-oxabicyclo / ^^ - o / octane - ^ - one, 6ml dihydropyran and ^ O mg p- Toluenesulfonic acid in 300ml abs. Methylene chloride, the mixture is stirred for 1 hour at 5 ° C. Then it is diluted with ether, shaken with sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. 21 g of the tetrahydropyranyl ether are obtained as a colorless oil.
IB: 2950, 2860, 1770, 1 ^ 58 / cm.

Ib) (IS, 3RS, 5R, 6S, 7R) -6-Benzyloxymethyl-3-hydroxy-7- (tetrahydropyran-2-yloxy) -2-oxabicyclo / 3-3.0 / octane

To a solution of 21g of the product prepared according to reference example la in 9 ^ OmI abs. Toluene is added dropwise at -70 ⁰ under argon löOml 1.2 M solution of diisobutylaluminum hydride in toluene. The mixture is stirred for 30 minutes at -70 ° C., 5 ml of isopropanol are added dropwise, the mixture is allowed to warm to -10, 70 ml of water are added, the mixture is stirred for 2 hours at room temperature, filtered and evaporated in vacuo. This gives 20 g of the lactol as a colorless oil.
IR: 3600, 3 ^ 00 (br.), 2950, 2860,

2-yloxy) cyclopentanol

To a solution of 28.6 g of methyltriphenylphosphonium bromide in abs. 77 ml of dimethyl sulfoxide (DMS6) are added dropwise at 15 ° C. under argon a 1.0 * 1- M solution of methylsulfinylmethylsodium in DMSO and stirs for one hour at room temperature. Then you add a Solution of 7g of the lactol prepared according to reference example Ib in 50ml abs. DMSO and stirred for 3 hours at room temperature. The mixture is stirred into 500 ml of ice water and extracted four times with 200 ml of a mixture each time from pentane / ether (l + l), washes the organic extract neutral with water dries over magnesium sulfate and evaporates in vacuo.

030018/0323

. ./13

-13-

The residue is purified by chromatography on silica gel with a pentane / ether gradient. 6.1 g of the cyclopentanol are obtained as a colorless oil.
IR: 3500, 29-0, 2855, 920, 968, 998 / cra.

Id) (lS, 2R, 3S, ^f fR) -3-ben2yloxymethyl-2- (prop-2-en-l-yl) -l-tosylox.Y- ⁱ f- (tetrahydropyran-2-yloxy) -cyclopentane

13.6 g of p-toluenesulfonyl chloride are added to a solution of 12.5 g of the alcohol prepared according to Reference Example Ic in 36 ml of pyridine and the mixture is stirred for 2 days at room temperature under argon. Then 6ml ice water is added, the mixture is stirred for 2 hours at room temperature, diluted with 0.6 l ether and shaken one after the other with water, ice-cold k% ± ger sulfuric acid, water, 5% NaHCO ^ solution, 3x with water. It is dried over magnesium sulfate and evaporated in vacuo. 17 μg of the tosylate are obtained as a colorless oil. IR: 2950, 2863, 1600, 1365, 1175, 903 / cm.

Ie) (lR, 2R, 3S, ^ R) -3-penzyloxymethyl-2- (prop-2-en-l-yl) - * t ~ tetrahydropyran-2-yloxy) -cyclopentanol

To a solution of 17 g of the tosylate prepared according to Id in 500 ml DMSO is added 51g of potassium nitrite and stirred for 2.5 hours at 65 ⁰ C under argon. It is then poured onto a 20% sodium chloride solution, extracted 5 times with 250 ml of a mixture of pentane / ether (1 + 1) each time, the organic phase is washed three times with 100 ml of brine each time, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel, 718 g of the inverted alcohol are obtained as a colorless oil with ether / pentane (3 + 2).
IR: 36OO, 3 ^ 50, 2950, 286 * 1- 1000 97Jf ₁ 9l8 / cm.

2-yloxy) -l-tosyloxy-cyclopentane

In analogy to reference example Id, 6.8 g of that prepared according to Ie are obtained Alcohol 9.5 g of the tosylate as a colorless oil. IR: 2950, 2863, 16 ^ 5, 1602, 1375, 1177, 975, 910 / cm.

.- / 19

030018 / ^ 23

Ig) (IS, 23.3S ₁ ^ B) -I- (bis-ethoxycarbonyl) -methyl-3-benzyloxymethyl ~ 2- (prop-2-en-1-yl) - *) ■ - (tetrahydropyran ^ -yloxy -cyclopentane 10.6 g of potassium t-butoxide are added to a solution of 30.2 g of diethyl malonate in 125 ml of t-butanol and the mixture is stirred for 1 hour at 60-80 ° C., then a solution of 9.5 g of the tosylate prepared according to If is added in 5 ml of fc-butanol and stirred for 26 hours under reflux and argon, then diluted with ether, washed neutral with water, dried over magnesium sulphate and evaporated in vacuo Volatile constituents from 60 ° -80 ° C. After purification by chromatography on silica gel with pentane / ethyl acetate C ^ + 1), 5.5 g of the above diester are obtained as a colorless oil.
IR: 2950, 2860, 1750, 1730, 16 ^ 2, 973, 915 / cm.

lh) (IR, 2S, 3S ₁ IfR) -I- Äthoxycarbonylme thyl- 3-benz; rloxymethyl-2- (prop-2- enl- ^ l) - ⁱ f- (tetrahydropyran-2-yloxy) -cyclopentane 4, 60 g of the diester prepared according to the reference example, 1.06 g of sodium cyanide in 30 ml of DMSO is stirred for 20 hours at 150 g under argon, then it is diluted with 3CO ml of a mixture of ether / pentane (l + l), shaken three times with 50 ml of water each time and dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel, 2.80 g of the monoester are obtained as a colorless oil with pentane / ethyl acetate (9 + 1).
IR: 2950, 2860, 1730, 1643, 973, 916 / cm.

Ii) (IR, 25.3S ₇ ^ R) -I-ethoxycarbonylmethyl-3-benzyloxymethyl-2-formylmethyl-4- (tetrahydropyran-2-yloxy) -cyclopentane

To a solution of 2.5 g of that prepared according to reference example lh) Esters in 31 ml of tetrahydrofuran and 7.8 ml of water are added at 25 ° C. to a solution of 16 mg of osmium tetraxide in 2 ml of tetrahydrofuran. Afterward 3.2 g of sodium periodate are added in portions over the course of 45 minutes, stir for 30 minutes at 25 C, filtered, diluted with ether, shakes once with dilute sodium hydrogen sulfite solution and washes neutral with water. It is dried over magnesium sulfate and evaporated in Vacuum a. This gives 2.48 g of the aldehyde as a pale yellow oil. IR: 2950, 286Ο, 2730, 1725, 970 / cm.

10Ö18 / U323

Ij) (IR, 2S, 3S ₁ ^ R) -I-ethoxycarbonylmethyl ^ -benzyloxy-methyl ^ -carboxymethyl- ^ - Ctetrahydropyran-Z-yloxy ^ cyclopentane To a solution of 2.5g of the aldehyde prepared according to Ii in 60 ml of acetone 2.5 ml of Jones reagent are added dropwise at 5 C and the mixture is stirred for 3 minutes at 5 C. Excess reagent is then added by the dropwise addition of isopropanol, stirred for 5 minutes, diluted with ether and washed with water until neutral, dried over magnesium sulfate, evaporated in vacuo and the residue was purified by column chromatography on silica gel. With pentane / ethyl acetate (3 + 2), 1.9 g of the carboxylic acid are obtained as a colorless oil.
IR: 3500 (broad), 2950, 2660, 1725, 970 / cm.

Ik) (lR, 2S ₁ 3S, ^ R) -l-ethoxycarbonylmethyl-3-ben2yloxy-methyl-2-methox7; · - carbonyl-4- (tetrahydropyran-2-yloxy) -cyclopentane To a solution of 1.3 g the acid prepared according to reference example Ij in 30 ml of methylene chloride is added dropwise at ice bath temperature 7 ml of an ethereal diazomethane solution, stirred for 3 minutes and evaporated in vacuo.

1.3 g of the methyl ester are obtained as a colorless oil. IR: 2958, 2860, 1731, 970 / cm.

11) (IR, 5S, 6S, 7R) -6-Benzyloxymethyl-7- (tetrahydropyran-2-yloxy) bicyclo / 3 »3» Q7octan-3-one

A mixture of 1.3 g of the diester prepared according to reference example Ik and 3 g of potassium tert-butoxide in 60 ml of tetrahydrofuran are stirred for 3 hours at room temperature under argon. Then acidify with 10 $> oiger Citric acid solution to pH 5, dilute with ether and wash with Water neutral. It is dried over magnesium sulfate and evaporated in vacuo. This gives 1.2 g of a mixture of the stereoisomer ß-ketoesters.

For decarbalkoxylation the crude product is dissolved in 2h ml of xylene, is 2 * fg!, Jf-diazabicyclo /2.2.2/octan added and stirred for h hours at I60 bath temperature under argon. Then it is diluted with ether, shaken one after the other with water, ice-cold 3 / ° strength sulfuric acid, sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated in vacuo. 90 mg of the ketone is obtained as a pale yellow oil. IR: 2935, 2860, 1735, 970 / cm.

030018/0323

../21

Im) (IR, 5S, 7R) -6 ~ BeKzyloxymethyl-7-hydroxy-bicyclo / 5 »5.0 / octan-3-one 0.9 g of the ketone prepared according to Example 11 is stirred for 3 hours at ^ 5 ° C with 17 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35 / lo) and then evaporated in vacuo. The residue is purified by chromatography on silica gel. With pentane / ethyl acetate (3 + 2), 0.68 g of the alcohol is obtained as a colorless oil. IR: 35 ^ 0, 2935, 2860, 1739, 1095 / cm.

In) (IR, 5S, 6S, 7R) -7-bengoyloxy-6-benzyloxymethyl-bicyclo / 3.3.07octan-3- one , 5 ml of benzoyl chloride, stirred for h hours at 25 ° C, treated with 0, ^ ml of water, stirred for 2 hours, diluted with ether, shaken successively with water, 5 ^ sulfuric acid, water, if ^ strength sodium bicarbonate solution and three times with water. After drying over magnesium sulfate, it is evaporated in vacuo and 720 mg of the benzoate are obtained as a colorless oil.
IR: 29 ^ 5, 2860, 1739, 1713, 1602, I588, 1276 / cra.

lo) (IR, 5S, 6S, 7R) -7-benzoyloxy-6-hydroxymethyl-bicyclo / 3.3.Q7octan-3-one A solution of 68O mg of the benzoate prepared according to the reference example In in 10 ml of ethyl acetate and 0.5 ml of glacial acetic acid is mixed with 120 mg of palladium on carbon (10 ^ ig) and shaken for 8 hours under a hydrogen atmosphere. After filtering and evaporating the solution in vacuo, 600 mg of an oily crude product are obtained, which is purified by chromatography on silica gel with pentane / ethyl acetate (1 + 1) and 395 mg of the clean alcohol as a colorless oil. IR: 3500, 29 ^ 5, 1739, I712, 1602, I588, 1278 / cm.

Ip) (IR, 5s, 6S, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-hydroxymethyl-bicyclo / 5 »3» 07octane

320 mg of the alcohol prepared according to Example 10, 0.5 ml of ethylene glycol, k mg of p-toluenesulfonic acid and 10 ml of benzene are stirred for 1.5 hours with a water separator at reflux temperature. It is cooled, diluted with ether, shaken once with sodium bicarbonate solution, washed neutral with water, dried over magnesium sulphate and evaporated in vacuo. This gives 390 mg of the ketal as a colorless oil. IR: 3500, 29 ^ 5, 2882, 1708, l60if, 1588, 1280, 9if8 / cm.

030018/0323

Iq) (IR, gS, 6R, 7R) -5,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 5.3-07-octane

To a solution of 5 A g Collins reagent in 6JmI abs. Methylene chloride is added dropwise with stirring at 5 ° C. to a solution of 1.03 g of the ketal prepared according to reference example Ip in 32 ml of abs. Methylene chloride and
Stir for 20 minutes at 5 ° C. Then, it is diluted with ether, shaken three times with sodium bicarbonate solution, three times with brine, dried over magnesium sulphate and evaporated at 25 ° C. in vacuo. 8 ^ 0 mg of the aldehyde are obtained as a yellow oil.
IR: 296O, 273O, I72O, I6O3, 1588, 1275, 948 / cm.

030018/0323

example 1

5 - {(E) - (IS, 5S, 6R, 7H) -7-Hydroxy-6-AE) ~ (3S) -3-hydroxy-1-octenyl7-bieyclo / 3-3-07octan-3-ylidene-pentanoic acid

To a solution of 3.04 g of 4-carboxylbutyltriphenylphosphonium bromide in 6ml 12 ml of dry dimethyl sulfoxide (DMSO) are added dropwise at 15 ° C. under argon a 1.04 molar solution of methylsulfinylmethylsodium in DMSO and stir 30 minutes at room temperature. A solution is added dropwise to the red ylene solution of 495 mg (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / * (E) - (3S) -3- (tetrahydropyran-2-yloxy) -l-octenyl / - bicyclo / 3-3-07-octan-3-one in 3ml abs. DMSO and stir at 45 ° C for 2 hours. The reaction mixture is poured onto ice water, acidified to pH 4-5 with 1 of the above citric acid solution and three times with Extracted methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel is obtained with ether / pentane (3 + 2) 462 mg of the olefination product, which is added to. Cleavage of the protective groups with 15 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) Stirred at 25 ° C. for 20 hours. It is evaporated in vacuo and chromatographed the residue on silica gel. Obtained with methylene chloride / isopropanol (95 + 5) one first 65mg 5 - ((Z) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3S) -3-hydroxy-1-octenyl7-bicyclo / 3-3.0_ / octan-3-ylidene ^ pentanoic acid (Melting point 95 ° C) and, as a lighter component, 103 mg of the title compound as a colorless oil. IR: 3600, 3450 (broad), 2940, 2865, 1712, 16O4, 975 / cm.

The starting material for the above title compound is prepared as follows: la) (lR, 5S, 6R, 7R) -3,5-ethylenedioxy-7-benzoyloxy-6 - / (E) -3-oxo-l-octenyl7- bicyclo / 3.3 "0.7 octane

To a suspension of 126 mg sodium hydride (55 ^ suspension in oil) in 11ml dimethoxyethane (abs.) (DME) is added dropwise at room temperature a solution of 664 mg of 2-oxo-heptylphosphonsäuredimethylester in 5 ₅ 5 ml DME (abs.), stir for 10 minutes, add 121 mg of lithium chloride and stir for 2 hours at room temperature under argon. Is then added at -20 ⁰ C with a solution of 755 mg of the aldehyde prepared in Reference Example Ig in 11ml DME (abs.) And stirred for 2.5 hours at room temperature under argon. The reaction mixture is then poured into 120 ml

030018/0323

28 A 5770

seeded ti pt c ammonium chloride solution, extracted three times with ether, the organic extract was washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel. With ether / pentane (1 + 1), 795 mg of the title compound are obtained as a colorless oil.
IE: 2940, 2862, 1715, 1670, 1628, 1275, 979, 948 / cm.

Ib) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-bensoyloxy-6 - / (E) - (5S) -5-hydroxy-loctenyl / -bicyclo / 3 »3-o / octane

To a solution of 790 rag of the ketone prepared according to Example la 420 mg of sodium borohydride are added in portions at -40 ° C. to 24 ml of methanol and stir for 1 hour at -40 C under argon. Then diluted it is washed with ether, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. By column chromatography on silica gel with Aether / pentane (7 + 3) is initially obtained 245 mf: the title compound as colorless oil. 152 mg of (IE, 5S, 6R, 7R) -3,3-ethylenedio "y-7-beri2oyloxy-6 - / (E) - (5R) -3-hydroxy-1-octenyl / bicyclo are obtained as the more polar component /3.3-O/octane.

IR: 36IO, 34OO (broad), 29 ¹ IO, 1715, 16'O4, 1538, 1279, 971,

lc) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-hydroxy-6 - / (E) - (5S) -3-hydroxy-l-octenyl / -bicyclo / 3 · 3 »0 / octane

A mixture of 500 mg of the α-alcohol prepared according to Example Ib and 333 mg of potassium carbonate (anhydrous) in 35 ^ra l of methanol is stirred for 16 hours at room temperature under argon. Then it is concentrated in vacuo, diluted with ether and washed neutral with brine. It is dried over magnesium sulphate and evaporated in vacuo. This gives 495% of the title compound as a colorless oil (crude product).
IR: 3600, 5450 (broad), 2940, 975, 948 / cm.

Id) (IR, 5S, 6R, 7E) -7-hydroxy-6 - / (E) - (3S) -5-hydroxy-1-octenyl / -bicyclo / 3.3.0 / octan-3-one

495 mg of the diol prepared according to Example Ic are stirred for 22 hours 18 ml of a mixture of acetic acid / tetrahydrofuran / water (65 + 10 + 35). It is then evaporated in vacuo with the addition of toluene, the

ORIGINAL INSPECTED

030018/0323 .- / ^

ORIGINAL INSPECTED COPY

Residue in methylene chloride, shaken twice with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with ethyl acetate / pentane (9 + 1). This gives 282 mg of the title compound as a colorless oil.
IR: 3660, 36IO, 29 ^ 0, 2870, 1739, 973 / cm.

Ie) (IR, $ S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S) -3- (tetrahydropyran-2-yloxy) -l-octenyl / -bicyclo /3.3»Q7octan-3-on A solution of 260 mg of the ketone prepared in example Id, 0,36ml of dihydropyran and 2.5 mg of p-toluenesulfonic acid in 11 ml of methylene chloride is stirred for 20 minutes at 3 C. then it is diluted with ether, shakes with f / o sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. This gives ^ 90 mg of bis-tetrahydropyranyl ether, which is used for the Wittig reaction without further purification.
IR: 2955, 2862, 1739, 970 / cm.

Example 2

5-f (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6-AE) - (3R ^ RS) -3-hydroxy - ^ - methyl-1-octenyl / -bicyclo / 3.3 »07octane -3-yiiden ^ -pentanoic acid

Zk ml of a 1.0 ^ f molar solution of methylsulf inylmethylnatriuni in DMSO is added dropwise at 15 C under argon to 6.1 g ^ -Carhoxybutyltriphenylphosphoniumbromid in 12ml DMSO abs. and stir for 3 ° minutes at room temperature. A solution of 0.95 g (1R, 5S, 6R, 7R) ~ 7- (tetrahydropyran-2-yloxy) -6 - / "(E) - (3R, i ^ RS) - ^ - is added dropwise to the red ylene solution methyl-3- (tetrahydropyran-2-yloxy) -l-octenyl7-bicyclo / 3.3. q7 octan-3-one in 6 ml of absolute DMSO and stir for 2 hours at ^ 5 C. The reaction mixture is poured onto ice water, acidified with 10 citric acid solution to pH h-3 and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with ether / pentane (3 + 2) 0, 89 g of the olefination product, which is stirred with 28 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) to split off the protective groups.

030018/0323 ../26

graph the residue on silica gel · With methylene chloride / isopropanol

(95 + 5) you get 1 ^ 2 mg 5-i (Z) - (lS, 5S, 6fi, 7R) -7-hydroxy ~ 6 - / (E) - (3R, ifES) -3-hydroxy- ⁱ f-methyl-l-octenyl7-bicyclo / 3-3.0 / octan-3-ylidene? · pentanoic acid and, as the more polar component 230, the title compound stands out as a colorless oil.

IR: 36IO, 3 ¥ fO (broad), 29 ^ 0, 2860, 1712, 976 / cm.

The starting material for the above title compound is prepared as follows: 2a) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / (E) - ( ^f fRS) - ⁱ f- methyl-3-oxo-1-octenyl / bicyclo / 3.3-Q / octane

In analogy to Example la, 1.5 g of that according to the reference example is obtained Ig produced aldehyde and 1,3 S 3-methyl-2-oxoheptane-phosphonic acid dimethyl ester 1.62 g of the title compound as a colorless oil. IR: 29 ^ 0, 2860, 1715, I672, I628, 1275, 978, 9Wcm.

2b) (IR, 5S, 6B, 7R) -3,3-A'thylenedioxy -7-benzoyloxy-6 - / "(E) - (3R, ^ - RS) -3-hydroxy- * ^ ■ -meth .yl-l-octenyl7-bicyclo / 3.3 ^ Q / octane

To a solution of 1.50 g of the ketone prepared according to Example 2a in k 8 ml of methanol are added at ~ k0 C portionwise 85O mg of sodium borohydride and stirred for 1 hour at - ^ OC under argon. Then it is diluted with ether, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. Column chromatography on silica gel with ether / pentane (7 + 3) initially gives 520 mg of the title compound (3 <x -hydroxy) and, as the more polar component, 320 mg of the isomeric 3β-hydroxy-configured compound.
IR: 36OO, 3 ^ 20 (broad), 29 ^ 0, 1715, 1603, 1588, 1278, 972, 9Wcm.

2c) (lR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-hydroxy-6-AE) - (3g, ^z l-RS) -3-hydroxy - ^ - methyl-l-octenyl / bicyclo / 3-3 »Q / octane

A mixture of 510 mg of the α-alcohol prepared according to Example 2b and 33Ο mg of potassium carbonate in 35 mg of methanol is stirred for 18 hours at room temperature under argon. Then it is concentrated in vacuo, diluted with ether and washed neutral with brine. It is dried over magnesium sulfate and evaporated in vacuo. This gives ^ 85 mg of the title compound as a colorless oil (crude product).
IR: 36OO, 3V30 (broad), 29 ^ 5, 976,

030018/0323

.- / 27

bicyclo / 3 »3 · O / octan-3-one

In analogy to Example 1d, 485 mg of the according to Example are obtained 2c produced diol 295 mg of the title compound as an oil.

IR: 3600, 3 * 1-00 (broad), 2940, 2865, 1740, 973 / cm.

2e) (IR, 5S, 6R, 7R) -7 ~ (tetrahydropyran-2-yloxy) -6-AE) - (3R, 4SS) -4-methyl-3- (tetrahydropyran-2-yloxy) -1-octenyl /-bicyclo/3.3-Q/octan-3-one In analogy to Example le, 460 mg of the bis-tetrahydropyranyl ether, which is used for the Wittig reaction without further purification, are obtained from 280 mg of the ketone prepared according to Example 2d. IR: 296Ο, 286Ο, 17 ^ 0, 972 / cra.

Example 3

5-i (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3R, 4RS) -4-fluoro-3-hydroxy-1-octenyl / -bicyclo / 3.3 "Q / octan-3 ~ ylidene * pentanoic acid

To a solution of 4.55 g of 4-carboxybutyl triphenylphosphonium bromide in 10 ml of abs. DMSO is added dropwise at 15 ° C. under argon, 18 ml of a 1.04 molar solution of methylsulfinyl methyl sodium in DMSO and stirred for 30 minutes at room temperature. A solution of 745 mg (lR, 5S, 6R, 7R) -7-tetrahydropyran-2-yl-oxy) -6 - / (E) - (3R, 4RS) -4-fluoro-3- is added dropwise to the red ylene solution. (tetrahydropyran-2-yloxy) -l-octenyl / bicyclo / 3.3 »Q7 ^octan -3-one in 5 ml abs. DMSO and stir at 45 ° C for 2 hours. The reaction mixture is poured onto ice water, acidified to pH 4-5 with 10 ^ citric acid solution and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with ether / pentane (3 + 2), 620 mg of the olefination product is obtained, which is used to split off the protective groups with 22 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) at 25 ° for 20 hours C stirs. It is evaporated in vacuo and the residue is chromatographed on silica gel. With methylene chloride / isopropanol (95 + 5), initially 122 mg of 5 - ((Z) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3R, 4ES) -4 are obtained -fluoro-3-hydroxy-loctenylZ-bicyclo / ^ OO / octaiv - ^ - ylidenT-pentanoic acid and, as a more polar component, 208 mg of the title compound as a colorless oil.IR: 3600, 3440 (broad), 2945, 2860, 1713, 976 / cm.

03 0 018/0323

The starting material for the above title compound is prepared as follows: 3a) (lR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / '(E) - (^ RS) - ^ - fluor- 3-oxol-octenyl / bicyclo / 3-3-O / octane

In analogy to Example la is obtained from 765 ^m S and ^the aldehyde prepared according to Reference Example Ig 665mg 3- £ ¹ luor-2-oxyheptanphosphonsäuredimethylester 620 rag of the title compound as a colorless oil. IR: 29 ^ 5, 2860, 1715, I67O, I63O, 1276, 979, 9Wcm.

3b) (IR, 5S, 6R, 7R) -3,3-A "thylenedioxy-7-benzoyloxy-6- / ^r (E) - (5R, ^ RS) - ⁱ f-fluoro-3-hydroxy-lo et enyl / -bi cyclo / 3.3 ■ 0_ / octane

In analogy to Example Ib, 1–6 mg of the title compound are obtained from ^ fIO mg of the ketone prepared according to Example 3 & 23Ο mg of sodium borohydride as a colorless oil.
IR: 3600, 3U10 (broad), 29 ^ 5, 2365, 1715, 160 * f, 1590, 1278, 97h, 9hS / cm.

hydroxy-1-octenyl7-bicyclo / 3 »3« O / octane

In analogy to Example Ic, 525 mg of that according to Example 3b are obtained produced α-alcohol and 3 ^ 0 mg potassium carbonate ^ 90 mg of the title compound than oil.

IR: 36ΟΟ, 3 ^ fOO (broad), 2950, 2865, 976, 9 ^ 8 / cm.

3d) (lR, 5S, 6R, 7R) -7-hydroxy-6 - / '(E) - (3RΛRS) - ^z ^ -fluoro-3-hydroxy-l-octenyl / -

In analogy to Example Id, 70 mg of that according to Example 3c is obtained produced diol 285 mg of the title compound as an oil. IR: 36ΟΟ, 3 * f20 (wide), 29 ^ 5, 2865, 17 ^ 0, 975 / cm.

3e) (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6-Λs) - (3RΛRS) - ² ^ -fluoro-3- (tetrahydropyran-2-yloxy) -l-octenyl7- bicyclo / 3.3-0 / octan-3-one In analogy to Example Ie, from 285 mg of the ketone prepared according to Example 3d, 70 mg of bis-tetrahydropyranyl ether (crude product), which is used for the Wittig reaction without further purification, is obtained. IR: 296Ο, 2360, 17 * fC, 975 / cm.

../29

030018/0323

example k

bicyclo / 3.3 »0 / octane-5-alidenepentanoic acid

36 ml of a 1.0 molar solution of methylsulfinylmethylnatriura in DMSO are added dropwise at 15 ° C. under argon to 9.2 g of if-carboxybutyltriphenylphosphonium bromide in 20 ml of abs. DKSO and stir for 30 minutes at room temperature. A solution of 1.5 g (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3R) - ⁱ ) -, ⁱ t is added dropwise to the red ylene solution - methylene-3- (tetrahydropyran-2-yloxy) -l-octenyl / -bicyclo / ^ - ^ - oyoctan ^ -one in 10 ml DMSO and stir for 2 hours at * f5 ° C. The reaction mixture is poured onto ice water, acidified to pH 5 with 10 ^ citric acid solution and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel, ether / pentane (3 + 2) gives 1.38 g of the olefination product, which is stirred with 35 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) to split off the protective groups. It is evaporated in vacuo and the residue is chromatographed on silica gel. With methylene chloride / isopropanol (95 + 5), 21o mg of 5 - {(Z) - (lS, 5S, 6R, 7R) -7-hydroxy ~ 6 - / (E) - (3R) -3 ~ hydroxy- * l -, * l · - methylen-l-octenyl / bicyclo / 3.3 · O / octan-3-ylidenr-pentanoic acid and, as a more polar component, 295 mg of the title compound as a colorless oil. IR: 3600, 3if50 (broad), 29 ^ 5, 2865, 1712, 976 / cnw

The starting material for the above title compound is prepared as follows: ka.) (IR, 5S, 6R, 7R) -5,3-ethylenedioxy-7-benzoyloxy-6 - / '(E) - ^f f, ^ - methylene - ^ - cocol-octenyl7-bicyclo / 3 "3" Q / octane

In analogy to example la, 1.48 g of that according to the reference example is obtained Ig produced aldehyde and 1.3 g of 3,3-methylene-2-oxoheptanephosphonic acid dimethyl ester 1.55 g of the title compound as a colorless oil. IR: 29 ^ 0, 2860, I715, I67O, I63O, 1275, 9? 8 / cm.

(IR, 5S, 6R, 7R) -3,3-Ä "thylenedioxy-7-benzoyloxy-6 - /" (E) - (3R) -3-hydroxy- ⁱ <-, 4-methylene-1-octenyl. 7-bicyclo / 3'30 / octane

In analogy to Example Ib, 1, ^ 5 g of the according to Example ka are obtained. produced ketones and 85O g Katriuraborhydrid 51 ° mg of the title compound as a colorless oil.
IH: 36OO, 3if00 (broad), 29 ^ 5, 2860, 1715, I603, 1590, 1277, 973, 9 ^ / cni.

0 300 18/0323

../30

(lR, 5S, 6R, 7R) -3,3-A "thylenedioxy-7-hydroxy-6 - /" (E) - (3R) -3-hydrox.y-4,4-methylene-l-octenyl7- bicyclo / 3.3 »O / octane

In analogy to Example 1c, from ^ 90 mg of the α-alcohol prepared according to Example kb and 320 mg potassium carbonate ^ 70 mg of the title compound are obtained as a colorless oil.
IR: 3600, 3 ^ 00 (broad), 29 ¹ K), 2860, 976 / cm.

(lR, 5S, 6R, 7R) -7-hydroxy-6 - / * (E) - (3S) -3-h7 ^ droxy- ¹ t-, ¹ f-methylene-1-octenyl / ^r bicyclo / 3 »3» Q / octan-3-one

In analogy to Example Id, 280 mg of the compound compound are obtained as an oil from 70 mg of the diol prepared according to Example kc.

IR: 3600, -3 ^ 00 (wide), 29 ^ 5, 2860, l? 40, 97k / cm,

he) (IR, 5S, 6R, 7R) -7- (getrahydropyran-2-yloxy) -6 - / (E) - (3R) ^-1 l-, ^f f -methylene-3- (tetrahydropyran-2-yloxy ) -l-octenyl / -bicycI.o / 3 »3-Q / octan-3-one In analogy to Example Ie, from 270 mg of the ketone prepared according to Example ka , VtO mg of bis-tetrahydropyranyl ether, which can be obtained without further purification for Wittig - olefin is used. IR: 2960, 2860, 1739, 975 / cm.

example 5

3-f (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6-Z ^- (E) - (3S) -3-hydroxy-1-nonenylA-bicyclo / 3 »3-0 / octane -3-ylidene) pentanoic acid

To a solution of 3 _> 3 ⁱ f · g ^ -carboxybutyl-triphenylphosphonium bromide in 6.5 ml of abs. DMSO is added dropwise to 13.2 ml of a 1.04 M solution of methylsulfinylsodium in DMSO at 15 ° C. under argon. After 15 minutes, a solution of 500 mg (IR, 5 ^s , 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / "(E) - (3S) -3- (tetrahydropyran) is added dropwise to this ylene solution -2-yloxy) -l-nonenyl / -bicyclo / 3.3.0 / octan-3-one in 3 nil absolute DMSO and heated for 2 hours to ^ 5-50 ° C. It is then poured into ice water, acidified with citric acid to pH 5 and extracted with methylene chloride. The extract is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel with an ether / pentane mixture gives 35 mg of a yellow oil, which is

030018/0323 ../31

Cleavage of the protective groups with 15ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) is stirred at ^ 0 ⁰ C for 16 hours. After evaporating the solution, the residue is chromatographed on silica gel with methylene chloride / isopropanol (95 + 5). 80 mg of 5- C (Z) - (lS, 5S, 6R, 7R) -7-hydroxy-6- / ~ (E) - (3S) -3-hydroxy-l-nonenyl / -bicyclo / 3.3 are obtained. Q / octan-3-ylidene? pentanoic acid and, as the more polar component, 120 mg of the title compound as a colorless viscous oil.
IB: 3600.3 ^ 55 (wide), 29 ^ 5, 2865, I7I0, 978 / cm.

The starting material for the title compound is prepared as follows: 5a) (lR, 5S, 6R, 7R) -3r3-ethylenedioxy-7-benzoyloxy-6 - / "(E) -3-oxo-l-nonenyl7-

252 mg of sodium hydride (55 °° ig) are suspended in 25 ml of abs. Dimethoxyethane and 1.39 g of 2-oxo-octylphosphonic acid dimethyl ester dissolved in 10 ml of dimethoxyethane are added dropwise at 15 C. The mixture is stirred for 10 minutes, 2 ^ 5 mg of lithium chloride are added and, after one hour at -20 ° C., a solution of 1.51 g of the aldehyde prepared according to reference example Ig in 25 ml of abs is added dropwise. Dimethoxyethane too. Mixture is then stirred for 2 hours at 10-15 C ₅ are in 250 ml of saturated ammonium chloride solution, extracted several times with ether, the organic extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with ether-hexane mixtures. 1. ^ 9 g of the above ketone are obtained as an oil.
IR: 29 ^ 5, 2860, 1715, 167O, 1630, 1275, 978,

5b) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy ~ 6 ~ f (E) - (3S) -3-hydroxy ~ inonenyl / -bicyclo / 3.3 -o / octane

To a solution of ~ L, kk g of the ketone prepared according to Example 5a in ^ O ml of methanol is added with stirring at ~ k0 C in portions, 800 mg of sodium borohydride, stirred for 1 hour at - ^ Q ⁰ C, diluted with 200 ml of ether, washed with .Neutral brine, dries over magnesium sulfate and evaporates in vacuo. The mixture of the epimeric alcohols is separated by chromatography on silica gel with hexane / A'tlier mixtures. As an impolar component, 576 mg of the desired (3S) -alcohol is obtained as an oil, and as a more polar component ^ 90 ml of (3R) -alcohol, also as an oil. IR: 36ΟΟ, 3if00 (broad), 29 ^ 5, 1715, 1602, 1588, 1275, 975, 9Wcm.

0S0018 / Ü323

_ ₃₂ _ 28A5770

5c) (IR, 5S, 6R ₁ 7R) -3,3-ethylenedioxy-7-hydroxy-6 - / "(E) - (3S) -3-hydroxy-inonenyl / -bi cyclo / 3.3 ♦ O / octane

500 mg of the (3S) alcohol from Example 5b are mixed with 35 ml of methanol 315 mg of potassium carbonate were stirred at 20 ° C. for 16 hours. After narrowing in Vacuum is diluted with 200 ml of ether, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. The raw product is used in the next stage without further purification.

5d) (IR, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3S) -3-hydroxy-1-nonenyJ-bicyclo / 3.3.0 / octane-3-cm

The crude product from Example 5c is stirred for 22 hours with 20 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo with the addition of toluene and the residue is chromatographed on silica gel with ethyl acetate / hexane mixtures. 270 mg of the above ketone are obtained as an oil.
IR: 3600, 29 ^ 5, 2870, V? KO, 975 / cm.

5e) (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6-AE) - (3S) -3- (tetrahydropyran-2-yloxy) -l-nonenyl / -bicyclo / 3- 3-Q / octan-3-one 250 mg of the ketone from Example 5d are stirred in 10 ml of methylene chloride with 0.35 nil dihydropyran and 2.5 mg of p-toluenesulfonic acid at 0-5 ° C. for 30 minutes. Then it is diluted with 100 ml of methylene chloride, shaken with sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. V? 5 mg of the bistrahydropyranyl ether are obtained as a yellow oil.
IR: 2955, 2860, 17 ¹ K) ₁ 972 / cm.

Example 6

5- $ (E) - (lS, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3R ^ RS) -3-hydroxy-Wethyl-l-nonenyl7- bicyclo / 3 «3 · O / octan-3-ylidene · pentanoic acid

In analogy to Example 5, hZO mg (IR, 5S, 6R, 7R) -7- (Tetrahydropyrai 2-yloxy) -6 - / (E) - (3R ₁ ^ -RS) -i) -methyl-3 is obtained - (tetrahydropyran-2-yloxy) -l-nonenyl / -bicyclo / 3.3.0 / octan-3-one 95 mg of the title compound and 85 mg of the Z-isomer 5 - ((Z) - (lS, 53,6R, 7R) -7-Hydroxy-6 - / (E) - (3R, ^z fRS) -3-hydroxy- ⁱ t-methyl-1-nonenyl / bicyclo / 3.3 o / octan-3-ylidene-pentanoic acid .

IR: (Ε-isomers): 36OO, 3 ^ 50 (broad), 29 ^ 5, 2860, 1710, 978 / cm.

030018/0323

../3 j

The starting material for the title compound is prepared as follows: 6a)

nonenyl / bicyclo / 3 «3» 0 / octane

In analogy to Example 5a, from 2g (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo / 3 »3» 0 / octane is obtained with 3-methyl-2-oxooctylphosphonic acid dimethyl ester 2.01 g of the above ketone as a viscous oil. IR: 2950, 2860, 1715, I67O, I63O, 1602, 1275, 978,

6b) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / '(E) - (3R, ^ RS) -3-hydroxy- ^ -methyl-1-nonenyl / -bicyclo / 3'3 »07octane

In analogy to Example 5b, 1.95 g of the ketone prepared according to Example 6a gives 800 mg of the above-mentioned (3R) -a-alcohol and, as the more polar portion, 730 mg of (3S) -ß-alcohol.
IR: 3600, 3 ^ 00 (broad), 2950, 1715, 16O2, 1588, I27O, 978,

6c) (lR, 5S, 6R _ί 7R) -3,3-ethylenedioxy-7-hydroxy-6 - / '(E) - (3RΛRS) -3-hydroxy-tfmethyl-l-nonerayl / -bicyclo / 3 -3 "Q / octane

In analogy to Example 1 5c, 790 mg of that according to Example 6b are obtained produced (3R) -a-alcohol 750 mg of the above diol as a crude product.

6d) (lR, 5S, 6R, 7R) -7-hydroxy-6 ~ / l: E) - (5R ^ RS) -3-hydroxy- ^ methyl ~ l-nonenyl7- bicyclo- / 3 »3-07ootan- 3-on

In analogy to Example 5d, 730 mg of that according to Example 6c are obtained produced diols' t20 mg of the above ketone as a colorless oil.

IR: 36ΟΟ, 295Ο, 287Ο, 17 ^ 0.978 / cm.

6e) (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3RΛRS) - ^ί ^ -methyl-3- (tetrahydropyran-2-yloxy) -l- nonenyl7-bicyclo / 3 · 3-Q7octan-3-one In analogy to Example 5e, 950 mg of the above-mentioned bis-tetrahydropyranyl ether are obtained as an oil from 700 mg of the ketone prepared according to Example 6d. IR: 2950, 286Ο, 17 ^ 0.978 / cm.

030018/0323

Example 7

5-f (E) - (IS, 5S, 65,7R) -7-hydroxy-6 - / "(E) - (3S) -3-hydroxy-4-phenyl-1-butenyl / -bicyclo / 3.3. 0 / octan-3-ylidene? -Pentanoic acid

A solution of 2.21g ^ -carboxybutyl triphenylphosphonium bromide in 5ml abs. DMSO is treated at 15 ° C. with 91.5 ml of a 1. Qh M solution of methylene sulfinyl sodium in DMSO. After 15 minutes, MfO mg (IR, 5S, 6R, 7B) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S) - ⁱ f-phenyl-3- (tetrahydropyran-2- yloxy) -l-butenyl / bicyclo / 3.3-0 / octan-3-one dissolved in 3 ml of abs. DMSO is added and stirred for 2 hours at 5Q C, then ice-water, provides with citric acid to pH k, 5 and extracted with methylene chloride. The extract is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After purification by chromatography on silica gel with hexane / ether mixtures, the protective groups are reacted with acetic acid (analogous to Example 5) and, after chromatographic purification on silica gel with methylene chloride / isopropanol (95 + 5), 75 mg of 5 - {(Z) - (IS, 5S, 6R, 7R) -7-Hydroxy-6- / ~ (E) - (3S) -3-hydroxy- ^/ f-phenyl-1-butenyl / -bicyclo / 3.3-Q / 'octane. -3-ylidene) pentanoic acid and, as the more polar component, 110 mg of the title compound as a colorless oil. IR: 36OO, 3 ^ 50 (broad), 29 ^ 5, 2860, 1710, 1602, 978 / cm.

The starting material for the title compound is prepared as follows: 7a) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / (E) -3-oxo-if-phenyl-butenyl /-bicyclo/3.3- O / octane

In analogy to Example 5a, 2.5 g (IE> 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo _J / 3 «3-0zoctane are obtained by reaction with the sodium salt of 2-0xo-3-phenyl-propylphosphonic acid dimethyl ester 2.5 g of the above ketone as an oil.
IR: 2955, 2870, 1712, I67O, I632, 1600, 1275, 975,

7b) (lR, 5S, bR, 7R) -5,3-ethylenedioxy-7-benzoyloxy-6 - / (E) - (3S) ^-3-hydroxy-f fphenyl 3rbutenyl / -bicyclo / 3.3. O / octane

In analogy to Example 5b, from 2. * fo g of the ketone prepared according to Example 7a, 1.05 g of the above (3S) -a-alcohol and, as a more polar portion, 0.95 g of (3R) -ß-alcohol.
IR: 3600, 3if00 (broad), 2950, 2865, 1712, 16O2, I58.8, 1270, 978, 9Wem.

030018/0323

7c) (IR, 5S, 6R, 7R) -3,3-A "thylenedioxy-7-hydroxy-6 - / '(E) - (3S) -3-hydroxy- * tphenyl-1-butenyl7-bicyclo / 3 "3" 0 / octane

In analogy to Example 5c, 1.02 g of that of Example 7b is obtained produced (3S) -a-alcohol 800 rag of the above diol as a crude product.

7d) (lR, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3S) -3-hydroxy- ⁱ l-phenyl-l-butenyl7-bicyclo / 3 »3» Q / octane 3-on

In analogy to Example 5d, 800 mg of that according to Example 7c are obtained produced diol 530 mg of the above ketone as a colorless oil. IR: 3600, 2950, 2865, 1738, 16O2, 975 / cm.

7e) (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S) - * f-phenyl-3- (tetrahydropyra.n-2-yloxy) - 1-butenyl / bicyclo / 3.3 »O / octan-3-one In analogy to Example 5e, 7OO mg of the above-mentioned bis-tetrahydropyranyl ether are obtained as an oil from 5OO mg of the ketone prepared according to Example 7d. IR: 2950, 2860, 1738, 1602, 976 / cm.

Example 8

5 - ^ (E) - (lS, 5S, 6R, 7R) -7-hydroxy-6- / l3R ^ RS) -3-hydroxy - ^ - methyl-l-octyl / -bicyclo / 3.3-Q / octan- 3-ylideneg-pentanoic acid

450 mg of (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / T (3R, ⁱ fKS) are added to a ylene solution, prepared from 3g '+ -carboxybutyl-triphenylphosphonium bromide analogously to Example 5 ) - ⁱ t -niethyl-3- (tetrahydropyran-2-yloxy) -loctyl7-bicyclo / 3o.Q7octan-3-one dissolved in 3 ml of abs. DMSO and stirred for 2 hours at 5 ° C. The mixture is diluted with ice water, acidified with citric acid to pH h, 5 and extracted several times with methylene chloride. The extracts are combined, shaken with brine, dried over magnesium sulfate and evaporated in vacuo. To remove the protective groups, the crude product is stirred for 6 hours at h3 C with 20 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10). After evaporation to dryness, the residue is chromatographed on silica gel with methylene chloride / 1-5% isopropanol. 80 mg of 5-f (Z) - (IS, 5S, 6R, 7K) -7-hydroxy-6 - / ^ R, ^ RS-J-hydroxy-V-methyll-octyl / -bicyclo / 3.3 «Q are obtained / octan-3-ylidene ^ pentanoic acid and, as the more polar component, 110 mg of the title compound as a colorless oil. IR: 3600, 3 * 1-50 (broad), 2950, 2860, 1710 / cm.

030018/0323

The starting material for the title compound is prepared as follows: 8a) (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / ^r (3RΛRS) - ^ί ^ -methyl-5- (tetrahydropyran- 2-yloxy) -l-octyl / -bicyclo / 3-5-0 / octan-3-one A solution of Ig (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / (E) - (3R, 4RS) - ⁱ -methyl-3- (tetraliydropyran-2-yloxy) -l-octenyl7-bicyclo / 3.3.07 octan-3-one in 25 ml of ethyl acetate is shaken up with 100 mg of palladium Coal (10 ^ ig) under a hydrogen atmosphere approx. 1 hour until 1 mole of hydrogen per mole of substrate is absorbed. After filtering and evaporating the solvent, the above compound is obtained as a pale yellow oil.
IR: 296O, 2865,

Example 9

5- ((E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(3S) -3-hydroxy-1-nonyl / -bicyclo / 3.3-Q / octan-3-yli den) · pentanoic acid

A ylene solution, prepared from 3.5 g of ^ -carboxybutyl-triphenylphosphonium bromide analogously to Example 5, is mixed with 500 mg of (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) - 3- (tetrahydropyran-2-yloxy) -l-nonyl / -bicyclo /3.3.07octan-3-one dissolved in 3 ral abs. DMSO and stir for 2 hours at 50 ° C. After dilution with ice water and acidified to pH k, 5 with citric acid then extracted several times with methylene chloride. The combined extracts are shaken with brine, dried over magnesium sulfate and evaporated in vacuo. To remove the protective groups, the crude product is stirred for 6 hours at ^ 5 ° C with 20 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10). After evaporation to dryness, the residue is chromatographed on silica gel with methylene chloride / 1-5% isopropanol. 100 mg of 5 - {(Z) - (lS, 5S, 6R, 7R) -7-hydroxy-6 - / "(3S) -3-hydroxy-l-nonyl / -bicyclo / 3.3.0 / octan- 3-ylidene) pentanoic acid and, as the more polar component, 120 mg of the title compound as a colorless oil.
IR: 3600, 3 * f55 (broad), 2950, 2865, 1710 / cm.

The starting material for the title compound is prepared as follows:

- / 37

030018/0323

9a) (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6-A3S) -3- (tetrahydropyran- 2-yloxy) -1-nonyiy-bicyclo / 3 »3» 0 / octane -3-one 800 mg (IE, 5S, 6E, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - / (E) - (3S) -3- (tetrahydropyran-2-yloxy) -l-nonenyl /-bicyclo/3.3·Q7octan-3-one (preparation see example 5e) dissolved in 20 ml of ethyl acetate are shaken with 80 mg of palladium on carbon (10 ^ ig) under a hydrogen atmosphere until 1 mol of hydrogen per mol of substrate is absorbed. After filtering and evaporating the solvent, the above compound is obtained as an oil. IE: 2965, 2865, 17 ^ 0 / cm.

Example 10

3 - ^ (E) - (lS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3S) -3-hydroxy-oct-l-en-6-ynyl / -bicyclo / 3.3.Q / octan-3-ylidene pentanoic acid

To a solution of 2.66 g of ^ -carboxybutyltriphenylphosphonium bromide in 6 ml of abs. 10.6 ml of a 1.0 ^ molar solution of methylsulfinylmethylsodium in DMSO are added dropwise to DMSO at 15 ° C. under argon and the mixture is stirred for 30 minutes at room temperature. A solution of VjO mg (lR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S) -3- (tetrahydropyran-2-yloxy) is added dropwise to the red ylene solution -oct-l-en-6-ynyl / -bicyclo. / 3 »3» Q7octan-3-one in 3 ml abs. DMSO and stir for 2 hours at V5 C. The reaction mixture is poured onto ice water, acidified to pH k ~ 3 with 10J citric acid solution and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel, ether / pentane (3 + 2) ml · 5 mg of the olelination product is obtained, which is used to split off the protective groups with 15 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) for 20 hours at 25 ⁰ C stirs. It is evaporated in vacuo and the residue is chromatographed on silica gel. With methylene chloride / isopropanol (95 + 5), 72 mg of 5 - {(E) - (IS, 5S, 6S, 7R) -7-hydroxy-6 - / '(Z) - (3S) -3-hydroxy are initially obtained -oct-l-en-6-ynyl7-bicyclo / 3.3-0 / octan-3-ylidene? -pentanoic acid and, as the more polar component, 121 mg of the title compound as a colorless oil.
IR: 36ΟΟ, 3if20 (broad), 29 ^ 5, 286Ο, 1712, 976 / cm.

Q30018 / 0323

The starting material for the above title compound is prepared as follows: 10a) (lR, 5S, 6R ₁ 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / (E) -3-oxo-oct-l- en-6-ynyl7- bicyclo / 3-3 »O / octane

In analogy to Example la, 5 ^ 0 mg of the according to the reference example is obtained Ig prepared aldehyde and 0.5 g of 2-0xo-hept-5-yn-phosphonic acid dimethyl ester 0.62 g of the title compound as a colorless oil.

IR: 29 * 1-5, 2860, 171 * 1 ·, I672, I63O, 1275, 978,

10b) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / "(E) - (3S) -3-hydroxy-octl-en-6-ynyl / -bicylco / 3 »3-0 / octane

In analogy to Example Ib, 135 mg of the title compound are obtained as a colorless oil from A-OOmg of the ketone prepared according to Example 10a and 220 mg sodium borohydride.
IR: 3600, 3 * fl0 (broad), 29 ^ 0, 2860, 1715, 16O3, 1590, I278, 972, 9Wcm.

10c) (IR _; 5S, 6R, 7R) -3 _< 3-ethylenedioxy-7-hydroxy-6- / ~ (E) - (3S) -3-hydroxy-oct-len-6-ynyl / -bicyclo /3.3.Q/octane

In analogy to Example Ic, 230 mg of the title compound are obtained as a colorless oil (crude product) from 2 ^ 0 mg of the α-alcohol prepared according to Example 10b and I65 mg of potassium carbonate.
IR: 36OO, 3MtO (broad), 29 ^ 5, 286O,

lOd) (lR, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3S) -3-hydroxy-oct-l-en-6-ynyl / -bicyclo / 3 »3-O / octan-3-one

In analogy to Example Id, 230 mg of that according to Example 10c are obtained produced diol 1 ^ 1 mg of the title compound as a colorless oil. IR: 36 ^ 0, 36IO, 29 ^ 5, 2865, 17 ^ 0, 97 from.

1Oe) (lR, 5S, 6R, 7R) -7- (tetrahydrope: tran-2-yloxy) -6 - / "(E) - (3S) -3- (tetrahydropyran-2-yloxy) -oct-l- en-6-ynyl / bicyclo / 3.3-O / octan-3-one In analogy to Example Ie, 230 mg of bis-tetrahydropyranyl ether, which can be used without further purification for the Wittig reaction is used.
IR: 296Ο, 286Ο, 17 * f0, 972 / cm.

0300 1 8/0323

., / 39

Example 11

5- ((E) - (IS, 5S, 6R, 7R) -7-Hydroxy-6 - / "(E) - (3R, kRS) -3-hydroxy-if-methyl-oct l-en-6- inyl / bicyclo / 3.5 "O / oetan-3-ylidene ^ pentanoic acid 21.3 ml of a 1, (A molar solution of methylsulfinylmethylsodium in DMSO and stirred for 30 minutes at room temperature. A solution of 87Ο mg (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / "( E) - (3R, itRS) - ^ - methyl-3- (tetrahydropyran-2-yloxy) -oct-l-en-6-ynyl / -bicyclo / 3.3 «9.7octan-3-one in 6ml abs. DMSO and Stir for 2 hours at 3 ° C. The reaction mixture is poured onto ice water, acidified to pH 5 with 10 citric acid solution and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo.

After chromatography of the residue on silica gel, ether / Pentane (3 + 2) 9 ^ 0 mg of the olefination product, which is used for cleavage of the protecting groups with 30 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + IO) is stirred at 25 ° C. for 20 hours. It is evaporated in vacuo and chromatographed the residue on silica gel. With methylene chloride / isopropanol (95 + 5) I65 mg 5 - ((Z) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / '(E) - (3RARS) -3-hydroxy-4-

methyl-oct-1-en-6-ynyl / bicyclo / 3.3 «07octan-3-ylidene-pentanoic acid and as more polar component 253 mg of the title compound as a colorless oil.

IR: 36ΟΟ, 3 * f00 (wide), 29 ^ 0, 286Ο, 1712, 975 / cm.

The starting material for the above title compound is prepared as follows: IIIa) (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / (E) - (^ RS) - ^ - methyl - 3-oxo-oct-1-en-6-ynyl / -bicyclo / 3.3-Q7octane In analogy to. Example la is obtained from 1.3 g of the aldehyde prepared according to reference example Ig and Ig 3-methyl-2-oxo-hept-5-yn.-phosphonic acid dimethyl ester 1, ^ 5 E of the title compound as an oil.

IE: 29 ^ 0, 286O, 1711+, I67O, I629, 1275, 978, 9Wem.

lib) (lR, 5S, 6R, 7R) -3i3-ethylenedioxy-7-benzoyloxy-6 - / "(E) - (3R, ^ RS) -3-hydroxy- ^J + - methyl-oct-l- en-6-ynyl7-bicyclo / 3.3.Q7octane In analogy to Example Ib, from 806 mg of the ketone prepared according to Example 11a and 50 mg of sodium borohydride, 38 mg of the title compound are obtained as a colorless oil.
IR: 36OO, 3 * + 00 (broad), 29 ^ 5, 286Ο, I715, 1602, 1589, I278, 973,

03Q-018/0323

lic) (lR, 5S, 6R, 7R) -3,3-AΊ: hylenedioxy-7-hydroxy-6 - / (E) - (5RΛRS) -3-hydroxy- k- methyl-oct-l-en-a -inylZ-bicyclo / g ^ 'Q / octan ^ -one.

In analogy to Example 1c, 465 mg of the title compound are obtained as an oil (raw product) from 500 mg of the α-alcohol prepared according to Example 1b and 3 ^ 0 mg of potassium carbonate.
IR: 3600, 3400 (broad), 2940, 2860, 976, 9Wcm.

lld) (lR, 5S, 6R, 7R) -7-hydroxy-6 - / "" (E) - (3R, ⁱ i-BS) -3-hydroxy - ^ - methyl-oct-l-en-6 -inyl / -bicyclo / 3 «3» Q7octan-3-one

In analogy to Example Id, 455 mg of the lic produced diol 295 mg of the title compound as a colorless oil. IR: 3600, 29 * 1-5, 2860, 1740, 9? 4 / cm.

lie) (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6-AE) - (3R, 4RS) -4-methyl- 3- (tetrahydropyran-2-yloxy) -oct-l -en-6-ynyl, ^7- bicyclo / 3.3-Q7octan-3-one In analogy to Example Ie, from 270 mg of the ketone prepared according to Example lld and 0.38 ml of dihydropyran 460 mg of bis-tetrahydropyranyl ether, which can be used without further purification the Wittig reaction is used.
IR: 2960, 2865, 1738, 975 / cm.

Example 12

5-f (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3RS) -3-hydroxy-3-methyl-oct-1-en-6- ynyl /-bicyclo/3.3Q7°ctan-3-yliden(-pentanoic acid 6 ml of a 1, ( AM solution of methylsulfinylmethylsodium in DMSO. After 15 minutes, 25Ο mg (IS, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3RS) -3-methyl- are added 3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl / -bicyclo / 3.3-Q / octan-3-one dissolved in 3ml abs.

DMSO and stir for 2 hours at 50 ° C. After diluting with ice water and acidifying to pH 4.5 with dilute citric acid solution is extracted several times with Methylene chloride, washes the extract with brine, dried over magnesium sulfate and evaporated in a vacuum. After chromatography of the residue on silica gel, with ether / pentane (1: 1) 270 mg of a crude product are obtained which are used for Cleavage of the protective groups with 8 ml of a mixture of acetic acid / water / Tetrahydrofuran (65/35 / IO) is stirred at 25 ° C. for 20 hours. Evaporate in vacuo

030018/0323 _{/ Ll}

~ ^kl ~ 284577Q

and chromatograph the residue on silica gel with methylene chloride / 1-5 $ isopropanol and initially receives 35 mg 5- £ (Z) - (lS, 5S, 6R, 7R) -7-hydroxy-

6 - / "(E) - (3RS) -3-hydroxy-3-methyl-oct-1-en-6-ynyl7-bicyclo / 3.3.o7octan-3-ylidene-i-pentanoic acid and as a more polar component 55 mg of the Title compound as a colorless oil.

IR: 3600, 3420 (broad), 2950, 2865, 1710, 978 / cm.

12a) (IB, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / ~ (E) - (3RS) -3-hydroxy-3-methyl-oct-1-en- 6-ynyl / -bicyclo / 3-3 »0.7oc-tan To a solution of h g (lR, 5S56R> 7S) -353-ethylenedioxy-7-ben2oyloxy-6 - / (E) -3-oxo-oct- 1-en-6-ynyl7-bicyclo / 3.3-Q7octane (preparation see example 10a) in 150 ml of abs. Tetrahydrofuran is added dropwise at -6O ⁰ C 30 ml of an ethereal solution of methylmagnesium bromide solution (manufactured from 0.1 mol magnesium), stirred for 15 minutes and then poured into 200 ml of saturated ammonium chloride solution, stirred for 10 minutes at 20 ⁰ C, extracted four times each 75 ml of ether, the combined extracts were washed twice with 30 ml of brine each time, dried over magnesium sulfate and evaporated in vacuo. After purification by column chromatography on silica gel with hexane / ethyl acetate mixtures, 315 g of the above alcohol are obtained as an oil. IR: 3600, 3 ^ 50 (broad), 2960, 2865, 1715, 1602, 1588, 1275, 976,

12b) (lR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-hydroxy-6 - / "(E) - (3RS) -3-hydroxy-3-metb.yl-oct-l- en-6-ynyl7-bicyclo / 3-3-Q /

A solution of 3.3 g of the alcohol prepared according to Example 12a in 300 ml of methanol is stirred for 16 hours at 25 ° C. with 2.5 6 potassium carbonate. The methanol is then evaporated off in vacuo, the residue is partitioned between methylene chloride and water / water, the organic phase is dried over magnesium sulfate and evaporated in vacuo. The residue is filtered through silica gel with hexane / ethyl acetate mixtures and 2.2o g of the above diol is obtained as a colorless oil.
IR: 3600, 3450 (broad), 2965, 2870, 978,

Ü30018 / 0323

12c) (IR, 5S, 6B, 7R) -7-hydroxy-6 - / "(E) - (3RS) -3-hydroxy-3-methyl-oet-1-en-6-ynyl / -bicyclo / 3 · 5 · o / -3-one

2 g of the diol prepared according to Example 12b are stirred for 20 hours 50 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10). It is evaporated in vacuo with the addition of toluene, the residue is taken up in methylene chloride and shaken successively with sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. 1.6 g of the above-mentioned ketone are obtained as an oil. IR: 3600, 3 ^ 50 (broad), 2965, 2860, 1738, 976 / cm.

12d) (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3RS) -3-methyl-3- (tetrahydropyran-2-yloxy) -oct-l -en-6-ynyl / -bicyclo / 3.3 «0 / ~ 3-one A mixture of Ig of the ketone prepared according to Example 12c, 50 ml of methylene chloride, 1.5 ml of dihydropyran and 10 mg of p-toluenesulfonic acid is stirred for 30 minutes at 0 -5 ° C. Then it is diluted with methylene chloride, shaken with sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with hexane / ethyl acetate mixtures and 1.25 g of the above-mentioned bis-tetrahydropyranyl ether is obtained as a colorless oil. IR: 2960, 2865, 1738, 978 / cm.

Example 13

5-C (E) - (lS, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3R, ^I <RS) ^-3-hydroxy-i i-methyl-oct-l- en- 6-ynyl7-bicyclo / 3.3-0 / oc ' ^t: an-3-yli <ien? -pentanoic acid methyl ester A solution of 100 mg 5- £ (E) - (IS, 5S, 6R, 7R) -7- Hydroxy-6 - / (E) - (3R, 4RS) -3-hydroxy- ⁱ t-methyl-oct-l-en-6-ynyl / -bicyClo / 3-3 «0 / octan-3-ylidene? - Pentanoic acid (for preparation, see Example 11) in 5 ml of methylene chloride is added dropwise with an ethereal diazomethane solution while stirring at 0 ° C. until it remains yellow. After evaporation of the solvent, the residue is purified by chromatography on silica gel with methylene chloride / l / o isopropanol and 90 mg of the title compound is obtained as an oil.

IR: 3600, 2960, 2865, 1735, 978 / cm.

0 3C018 / 0323

Example 1 ^ 4-

) - (IS, 5S, 6R, 7R) -7-Hydroxy-6 - / '(E) - (3R, ⁱ fRS) -3-hyd? Qxy - ^ - niethyl-oct-1-en-6-ynyl7 -bicyclo / 3 "3" Q7octan-3-ylidene ^ -pentanoic acid tri _r s (hydroxymethyl) aminomethane salt

To a solution of 360 mg of 5 - ((E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3R, * fRS) -3-hydroxy- ⁱ f-methyl -oct-l-en-6-ynyl7-bicyclo / 3.3.0 / octan-3-ylidenef-pentanoic acid (for preparation see Example 11) in 6O ml of acetonitrile is added at 65 ° C. to a solution of 121 mg of tris (hydroxymethyl) - aminomethane in 0.5 ml of water. The mixture is allowed to cool with stirring, after 16 hours the solvent is decanted and the residue is dried at 25 ° C. and 0.1 Torr. 320 mg of the title compound are obtained as a waxy mass.

030018/0323

ORIGINAL INSPECtEP

Claims (17)

Berlin, October 1st, 1978 New prostacyclin derivatives and processes for their preparation Patent claims
(l) | Prostane derivatives of the general formula I COOH, CH AWDEE ₂ where - * E is hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical can mean
A is a -CH ₂ -CH ₂ -, trans-CH = CH or -C ^ C group, W is a free or functionally modified hydroxymethylene group or C ¹ H a free or functionally modified ^ 3 -C- group, where the OH group 6h is α-constant, D and E together are a direct bond or D is a straight-chain or branched, saturated or unsaturated one Alkylene group with 1-10 carbon atoms, which is optionally substituted by fluorine atoms, E is an oxygen atom or a -C5C bond or a direct bond, R _{2 is} an alkyl, cycloalkyl, or an optionally substituted aryl or heterocyclic group, Rz is a free or functionally modified hydroxyl group, and if E _{1 has} the meaning of a hydrogen atom, its salts with physiologically compatible bases. 030018/0323 _{/ n} . .je. ORIGINAL INSPECTED 2) Process for the preparation of prostane derivatives of the general formula I, characterized in that a compound of the general formula II, s f II in which R _p , R ^., A, V /, D and E have the meanings given above, optionally after protecting any free hydroxyl groups present with a Wittig reagent of the general formula III Ph ₃ P = CH- (CH ₂ ) y-c'jj e wherein Eh denotes a phenyl group, reacts and optionally then separates isomers in any order and / or releases protected hydroxyl groups and / or esterifies or etherifies free hydroxyl groups and / or esterified a free carboxyl group and / or saponified an esterified carboxyl group or a carboxyl group with a physiological compatible base converted into a salt. 3) Medicines consisting of one or more compounds according to Claim 1 and customary auxiliaries and carriers. ¹ O 5 - [(E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3S) -3-hydroxy-1-octenyl7-bicyclo / 3-3« Q / octan-3-ylidene? -pentanoic acid 5) 5 - ((E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3R, ifRS) -3-hydroxy-if-methyl-loctenyl7-bicyclo / 3.3 -O / octan-3-ylidenefpentanoic acid 3 0 0 18/0323 6) 5 - ^ (E) - (lS, 5S, 6R, 7K) - ⁱ % ciroxy-6 - / (E) - (3R, ⁱ fRS) -4-fluoro-3-hydroxy-loctenyl / -bicyclo / 3.3- ° / octan-3-ylidene? -Pentanoic acid 7) 5 - {(E) - (IS, 5S, 6β, 7R) -7-Hydroxy-6-AE) - (3E) -3-hydroxy-if, ^ -methylene-loctenyl / -bicyclo / 3-3 -O / octan-3-ylidene-pentanoic acid 8) 5 - {(E) - (lS, 5S, 6R, 7R) -7-hydroxy-6-AE) - (3S) -3-hydroxy-l-nonenyl7-bicyclo / 3.3-0 / octane-3- ylidene> pentanoic acid 9) 5 - [(E) - (IS, 5S, 6R, 7R) -7-hydroxy-6- / ^r (E) - (3R, ⁱ fBS) -3-hydroxy-if-methyll-nonenyl / -bicyclo /3.30/octan-3-ylidenj -pentanoic acid 10) 5- £ (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / (E) - (3S) -3-hydroxy-it-phenyl-lbutenyl / ~ bicyclo / 3.3.o / octan-3-ylidene? -pentanoic acid 11) 5 - [(E) - (lS, 5S, 6R, 7R) -7-hydroxy-6 - / (3R, ifBS) -3 - hydroxy-ii ~ methyl-loctyl / -bicyclo / 3.3-Q / octan-3-ylidene ^ pentanoic acid 12) 5 - ^ (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(3S) -3-hydroxy-1-nonyl7-bicyclo / 3 · 3 · Q / octan-3-ylidene? -Pentanoic acid 13) 5 - ^ (E) - (lS, 5S, 6R, 7R) -7-hydroxy-6 - / '(E) - (3S) -3-hydroxy-oct-l-en-6-ynyl / - bicyclo / 3 »3 · o / octan-3-ylidem-pentanoic acid 1 * 0 5 - {(E) - (IS, 5S, 6R, 7R) -7-Hydroxy-6 - / "(E) - (3R, ifRS) -3-hydroxy-if-raethyloct-l-en- 6-iny! L7-bicyclo / 3-3-Q / octan-3-ylidene? -Pentanoic acid 15) 5-J (E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / "(E) - (3RS) -3-hydroxy-3-methyl-octl-en-6-ynyl / -bicyclo / 3-3'0 / oc: ⁱ ta-n-3-ylidenj-pentanoic acid 16) 5 - {(E) - (IS, 5S, 6R, 7R) -7-hydroxy-6 - / '(E) - (3R, itRS) -3-hydroxy-4-methyloct-1-en-6 -inyl / -bicyclo / 3-3 · Q / octan ~ 3-ylidenj-pentanoic acid methyl ester 17) 5 - ((E) - (IS, 5S, 6R, 7R) -7-hydroxy-6- oct-l-en-6-ynyl / bicyclo / 3.3-0 / octan-3-ylidene> -pentanoic acid-tris (hydroxymethyl) arainomethane salt "" ■ 18/03 ^ 3